By some estimates, nanotechnology promises to far exceed the impact of the Industrial Revolution and is projected to become a $1 trillion market by 2015. Engineered nanomaterials (NM) are already being used in sporting goods, tires, stain-resistant clothing, sunscreens, cosmetics and electronics and will also be utilized increasingly in medicine for purposes of diagnosis, imaging, and drug delivery.
Engineered nanomaterials are structures wherein the size of at least one dimension is 100 nanometer (nm) or less. The unique physicochemical properties of nanomaterials, such as engineered nanoparticles (NP), are attributable to their small size, large surface area, chemical composition, surface reactivity, surface charge, shape and media interactions. Although impressive from the perspective of material science, the novel properties of NM may lead to adverse biological effects, with the potential to create toxicity. Indeed, some studies have shown that NM can exert toxic effects and could pose hazards to humans and the environment (Service R F, Science 304:1732, 2004; Colvin V L, Nat Biotech 21:1166, 2003; Donaldson K, et al., Occup Environ Med 58:211, 2001; Oberdörster G, et al, Environ Health Perspect 113:823, 2005; The Royal Society. Nanoscience and nanotechnologies: Opportunities and uncertainties. www.royalsoc.ac.uk, July 2004 report). sed to NM.
Moreover, some NM, such as nanoparticles, readily travel throughout the body, deposit in target organs, penetrate cell membranes, lodge in mitochondria, and may trigger injurious responses. There is almost unanimous opinion among proponents and skeptics alike that the full potential of nanotechnology requires attention to safety issues. Environmental activists have called for a worldwide moratorium on NM research and marketing until protocols are in place to ensure worker safety.
While the properties of nanomaterials could necessitate a novel investigative approach to assess their hazard potential, research into air pollution and mineral dust particles has established a scientific basis for assessing lung and cardiovascular injury by inhaled particles. This includes evidence that ambient ultrafine particles (particulate matter with physical diameters <100 nm) induce reactive oxygen species (ROS), oxidative stress and inflammation in the lung and vasculature. Likewise, occupational exposure to quartz and mineral dust particles (e.g., coal and silicates) induces oxidative injury, inflammation, fibrosis, and cytotoxicity in the lung. Tissue and cell culture analysis support the in vivo outcomes, pointing to the role of ROS and oxidative stress in the generation of pro-inflammatory responses and cytotoxic effects. Taken together, these studies indicate that their small size, large surface area, chemical composition and ability to generate ROS play a key role in the ability of ambient NP to induce lung injury.
Although the heterogeneous characteristics of ambient ultrafine particles (UFP) are very different from the homogeneous composition of manufactured NP, the limited data on manufactured particles indicate that ROS production is also a key mechanism of toxicity. For instance, water soluble fullerenes induce O2 anions, lipid peroxidation, and cytotoxicity. Production of ROS, lipid peroxidation and the generation of pro-inflammatory responses have also been described in tissue culture and animal studies that addressed the potential toxicity of metal oxide particles (e.g., TiO2) and carbon nanotubes. This suggests that an investigation into the mechanisms of ROS production and their biological consequences could serve as a paradigm for investigating NP toxicity.
Oxidative stress is a state of redox disequilibrium in which ROS production overwhelms the antioxidant defense capacity of the cell, thereby leading to adverse biological consequences. Oxidative stress is often expressed in terms of the glutathione (GSH) to glutathione disulfide (GSSG) ratio in the cell. Not only does the GSH/GSSG redox couple serve as the chief homeostatic regulator of cellular redox balance but also functions as a sensor that triggers additional cellular responses which, depending on the rate and level of decline, could present as protective or injurious responses. The hierarchical oxidative stress model posits that minor levels of oxidative stress induce protective effects that may yield to more damaging effects at higher levels of oxidative stress. The protective cellular effects are regulated by the transcription factor, nuclear factor, erythroid 2-related factor 2 (Nrf2), which leads to transcriptional activation of >200 antioxidant and detoxification enzymes collectively known as the phase II response. Examples of phase II enzymes include heme oxygenase 1 (HO-1), glutathione-S-transferase (GST) isoenzymes, NADPH quinone oxidoreductase (NQO1), catalase, superoxide dismutase isoenzymes, glutathione peroxidase (GPx) and glucoronosyltransferase (UGT). Defects or aberrancy in this protective pathway could determine the susceptibility to particle-induced oxidant injury, e.g., the exacerbation of allergic inflammation and asthma by exposure to diesel exhaust particles (DEP). Should these protective responses fail to lead to adequate protection, a further increase in ROS production can result in pro-inflammatory and cytotoxic effects. Pro-inflammatory effects are mediated by the redox-sensitive MAP kinase and NF-kappa B cascades that lead to the expression of cytokines, chemokines and adhesion molecules. In contrast, cytotoxic effects are mediated by mitochondria, which are capable of releasing pro-apoptotic factors. Several types of NP have the capacity to target mitochondria directly.
Despite the intense interest in nanomaterial safety, no comprehensive test paradigm has been developed to compare the toxicity of different nanomaterials. Therefore there exists an urgent need to establish principles and test procedures to ensure the safe manufacturing and use of nanomaterials.